PROJECT SUMMARY/ABSTRACT Anomalous expression of glycosaminoglycans (GAG) such as chondroitin sulfate (CS) has been recognized in prostate cancer (PC) for decades. While CS is a potentially attractive tumor antigen in PC, utility of CS variants as therapeutic targets represent a technical challenge due to inherent low avidity of antibodies towards complex GAG structures. Embracing that challenge, we have developed a cross-disciplinary CS targeting strategy for PC based on engineered recombinant proteins from the malaria parasite Plasmodium falciparum. As a survival strategy to avoid host clearance, the malaria parasite has evolved a protein VAR2CSA that mediates high affinity binding to distinct CS in the placenta. PC express the same type of CS as placental trophoblasts thus recombinant malarial VAR2CSA (rVAR2) proteins can be re-purposed to target oncofetal CS (ofCS) modification in PC. Expression of ofCS in primary PC is not restricted to the tumor epithelium but is also present in the stromal cell compartment. Moreover, the rVAR2 protein can detect and isolate circulating tumor cells (CTCs) from complex blood samples. Finally, we have an rVAR2-Drug Conjugate (VDC886) able to engage ofCS-expressing PC cells in vitro and in vivo. Combined, our technology can access and target a tumor-selective GAG structure in PC for diagnostic and therapeutic applications. We hypothesize that our rVAR2-based ofCS-targeting system constitutes a novel therapeutic and diagnostic opportunity in human PC. Our hypothesis will be tested in the following Specific Aims: Aim 1: Preclinical evaluation of VDC886 as a novel treatment for metastatic CRPC (mCRPC). Aim 2: Visualization of metastatic PC lesions by ofCS PET imaging. Aim 3: Design and execute a phase I trial of VDC886 in mCRPC.